Nasal pharmaceutical formulations and methods of using the same

ABSTRACT

Nasal pharmaceutical formulations comprising a drug substance having a specific particle size distribution profile are disclosed herein. Such profile provides increased bioavailability, increased efficacy or prolonged therapeutic effect of the drug substance when administered intranasally. The formulations of the present invention may comprise one or more corticosteroids having a specific particle size distribution profile. In a preferred embodiment, the corticosteroid is beclomethasone or a pharmaceutically acceptable derivative thereof for the treatment of one or more symptoms of rhinitis. Preferably, the drug substance is beclomethasone dipropionate. The formulations herein may be provided as an aqueous suspension suitable for inhalation via the intranasal route.

CROSS REFERENCE TO RELATED APPLICATIONS

This is a continuation application of PCT/EP2004/003314, filed Mar. 29,2004, which claims the benefit of U.S. application Ser. No. 10/414,756,filed Apr. 16, 2003, which is incorporated herein by reference in itsentirety.

FIELD OF THE INVENTION

The present invention is directed to nasal pharmaceutical formulationscomprising a drug substance having a specific particle size distributionprofile. Such profile provides increased bioavailability, increasedefficacy or prolonged therapeutic effect of the drug substance whenadministered intranasally. In an alternative embodiment, formulations ofthe present invention comprise a beclomethasone or a pharmaceuticallyacceptable derivative thereof having a specific particle sizedistribution profile. The formulation may be provided as an aqueoussuspension suitable for intranasal administration to a subject in needthereof.

BACKGROUND OF THE INVENTION

It is known that the particle size of a drug substance affectsbioavailability of the drug and efficacy. Methods of making finelydivided drugs have been studied and efforts have been made to controlthe size and size range of drug particles in pharmaceuticalcompositions. However, the prior art does not disclose drug substanceshaving specific particle size distribution profiles which provideincreased bioavailability, increased efficacy or prolonged therapeuticeffect of the drug when administered intranasally.

It is known that inhaled corticosteroids are one of the most effectiveanti-inflammatory medications used in the treatment of respiratorydisorders or diseases characterized by inflammation. One suchcorticosteroid, beclomethasone dipropionate (BDP), is particularlyuseful in the treatment or prophylaxis of seasonal or perennial rhinitisand is also indicated for the relief of one or more symptoms associatedwith seasonal or perennial allergic and non-allergic (vasomotor)rhinitis. Rhinitis is a reaction that occurs in the eyes, nose andthroat when airborne irritants, for example, trigger the release ofhistamine. Histamine causes inflammation and fluid production in thefragile linings of nasal passages, sinuses and eyelids. Use ofcorticosteroids such as beclomethasone can cause partial or whole relieffrom rhinitis-related symptoms such as sneezing, congestion, runny nose,itchy nose, throat eyes and ears. Use of beclomethasone can also delaythe recurrence of nasal polyps in individuals who have undergone nasalpolyopectomy. In those polyps that do recur, beclomethasone can suppressthe polyp's growth increase in size.

Like most corticosteroids and other drug substances, BDP is veryslightly soluble in water. When such drug substances are administeredintranasally, they are typically suspended in an aqueous solution.However, when these substances are administered intranasally via aconventional nasal spray, less than optimal amounts of drug substance isabsorbed by the nasal mucosa (the target tissue), with the remainderbeing swallowed or expelled from the nasal cavity. In some instances,particles which are not sufficiently small are eliminated from thegastrointestinal tract before being disposed onto the target area. Theinability to administer optimal amounts of a drug substance results inreduced bioavailability and efficacy of that drug substance.

SUMMARY OF THE INVENTION

The present invention is directed to a nasal pharmaceutical formulationcomprising a drug substance having a specific particle size distributionprofile which provides increased bioavailability, increased efficacy orprolonged therapeutic effect of the drug substance when administeredintranasally. Specifically, in one alternative embodiment, theformulation of the present invention comprises a drug substance (e.g.,active ingredient) having the following particle size distributionprofile: about 10% of the drug substance particles have a particle sizeof about 0.75 microns; about than 25% of the drug substance particleshave a particle size of less than 1.5 microns; about 50% of the drugsubstance particles have a particle size of less than 2.0 microns; about75% of the drug substance particles have a particle size of less than3.5 microns; about 90% of the drug substance particles have a particlesize of less than 5.0 microns; and, greater than 90% or about 100% ofthe drug substance particles have a particle size of less than 10microns. In one alternative embodiment, the drug substance is acorticoid steroid, preferably beclomethasone or a pharmaceuticallyacceptable derivative thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the change from baseline in AM and PM reflective TNSS overtime in the ITT population over a 14 day study period.

FIG. 2 shows the change from baseline in AM reflective TNSS over time inthe ITT population over a 14 day study period.

FIG. 3 shows the change from baseline in PM reflective TNSS over time inthe ITT population over a 14 day study period.

FIG. 4 shows the change from baseline in AM and PM reflective TNSS overtime in the PP population over a 14 day study period.

DETAILED DESCRIPTION OF THE INVENTION

The formulations provided herein are used for treating, preventingand/or ameliorating one or more symptoms of a medical condition,disorder or disease. As used herein, treatment means any manner in whichone or more of the symptoms of the condition, disorder or disease areameliorated or otherwise beneficially altered. Treatment alsoencompasses any pharmaceutical or medicinal use of the formulationsherein. As used herein, amelioration of the symptoms of a particulardisorder by administration of a particular formulation refers to anylessening, whether permanent or temporary, lasting or transient that canbe attributed to or associated with administration of the formulation.As used herein, a “therapeutic effective amount” means a sufficientamount of drug substance to treat, prevent and/or ameliorate one or moresymptoms of a medical condition, disorder or disease. It also mayinclude a safe and tolerable amount of drug substance, as based onindustry and/or regulatory standards.

In one alternative embodiment, the formulations provided herein are usedfor treating, preventing and/or ameliorating one or more symptoms of arespiratory disorder in an individual. In another alternativeembodiment, the present invention provides a formulation for thetreatment, prophylaxis and/or amelioration of one or more symptoms ofrhinitis or other related disorders, wherein the formulation comprisesone or more corticosteroids having a specific particle size distributionprofile. In an alternative embodiment, the drug substance isbeclomethasone or a pharmaceutically acceptable derivative thereof.Preferably, the drug substance is beclomethasone dipropionate.Surprisingly, it has been found that a drug substance having the presentparticle size distribution profiles, when administered intranasally to asubject in need thereof, provides increased bioavailability of the drugsubstance, as well as increased and prolonged efficacy when compared toconventional formulations containing the same drug substance. Drugsubstances for use herein include any pharmaceutical compound having thepresent particle size distribution profile and capable of treating,preventing and/or amelioration one or more symptoms of a medicalcondition, disorder or disease when such substance is administeredintranasally to a subject in need thereof.

Mode of Administration

The present formulations may be packaged for administration in anyconventional manner, preferably in a nasal applicator, and preferably insuch a way as to deliver a fixed dose of drug substance (e.g., activeingredient). However, the present formulations may be administered via anasal application in such a way as to deliver a non-fixed dose of drugsubstance. Spray Administration containers for various types of nasalformulations have been known in the past and substantially all will beequally suitable for the present formulations, considering of coursethat the materials from which the container is made is compatible withthe formulations. The medium containing the drug substance and otherappropriate ingredients may be contained in a small bottle or similarcontainer, from which it can be dispersed as a mist to be directed intoeach nostril. Using ambient air as the propelling agent, one may havethe bottle made of a flexible plastic, so that merely squeezing thebottle's sides impels the spray out through the nozzle into the nasalcavity. Air may also be the propelling agent for a pump sprayer, inwhich the user manipulates a small pump button which pumps air into thecontainer and causes the liquid spray to be emitted on the returnstroke. Alternatively, the bottle can be pressurized with a gas which isinert to the user and to the ingredients of the solution. The gas may bedissolved under pressure in the container or may be generated bydissolution or reaction of a solid material which forms the gas as aproduct of dissolution or as a reaction product. Typical gases which canbe used include nitrogen, argon, and carbon dioxide. Also, when theformulation is administered as a spray or aerosol, the formulation maybe contained in a pressurized container with a liquid propellantincluding, but not limited to dicholorodifluoro methane orchlorotrifluoro ethylene, among other propellants.

In another alternative embodiment, for administration as a spray, thepresent formulations may be placed in an appropriate atomizing device,e.g. in a pump-atomiser or the like. The atomizing device may beprovided with appropriate means for delivery of aqueous spray to thenaris. Preferably, it is provided with means ensuring delivery of asubstantially fixed volume of composition/actuation (i.e. perspray-unit). In one embodiment, the device administers a metered dosage.The spray composition may be suspended or dissolved in a liquidpropellant. Stabilizing and/or suspending agents and/or co-solvents maybe present. In other embodiments herein, the formulation of the presentinvention is suitable for administration intranasally via a metered-dosespray pump to a subject in need thereof. In this respect, theformulation of the present invention may be pre-packaged in ametered-dose spray pump bottle, or metering atomizing pump.

In another alternative embodiment, the formulations of the presentinvention may be administered into the nose in the form of drops, or anyother method which results in topical application to the nasal mucosa.The form of dosage for intranasal administration may include solutions,suspensions or emulsions of the active compound in a liquid carrier inthe form of nose drops. Suitable liquid carriers include water,propylene glycol and other pharmaceutically acceptable alcohols. Foradministration in drop form formulations may suitably be put in acontainer provided e.g. with a conventional dropper/closure device, e.g.comprising a pipette or the like, preferably delivering a substantiallyfixed volume of composition/drop. The dosage forms may be sterilized, asrequired. The dosage forms may also contain adjuvants such aspreservatives, stabilizers, emulsifiers or suspending agents, wettingagents, salts for varying the osmotic pressure or buffers, as required.

In another alternative embodiment, the present formulations may beadministered in the form of a powder. For example, a powdery nasalcomposition can be directly used as a powder for a unit dosage form. Ifdesired, the powder can be filled in capsules such as hard gelatinecapsules. The contents of the capsule or single dose device may beadministered using e.g. an insufflator. Preferably, it is provided withmeans ensuring dosing of a substantially fixed amount ofcomposition/actuation.

Drug Substance

The present invention is directed to formulations for the treatment,prophylaxis, or amelioration of one or more symptoms of a condition,disorder or disease. In alternative embodiment, the present invention isdirected to formulations for the treatment, prophylaxis, or ameliorationof one or more symptoms of rhinitis or any other respiratory disorder.For example, the formulations disclosed herein are useful for thetreatment of seasonal allergic rhinitis (e.g., hay fever) or perennialallergic and nonallergic (vasomotor) rhinitis.

Drug substances suitable for use in the present formulations include anypharmaceutical—acceptable compound company or any of its derivativesincluding, but not limited to, any salts, esters, enol, esters, enolesters, acids, bases, solvates or hydrates thereof. Such derivatives maybe prepared by those of skill in the art using known methods for suchderivatization. Further, the drug substances for use in the formulationsand methods provided herein include those compounds comprising chiralcenters of either the (R) or (S) configuration, or a mixture thereof(e.g., racemate). Thus, the drug substances for use in the compositionsprovided herein include enantiomerically pure compounds, orstercoisomeric or diastereomeric mixtures thereof. It is to beunderstood that the chiral centers of the drug substances providedherein may undergo epimerization in vivo. Thus, one of skill in the artwill recognize that administration of a drug substance in its (R) formis equivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form.

Drug substances suitable for use in the present formulations include,but are not limited to, corticosteroids, such as beclomethasone and anyof its pharmaceutically acceptable derivatives. As used herein,pharmaceutically acceptable derivatives of a beclomethasone include anysalts, esters, enol ethers, enol esters, acids, bases, solvates orhydrates thereof. Such derivatives may be prepared by those of skill inthe art using known methods for such derivatization. Preferably, theformulations comprise beclomethasone dipropionate or its monohydrate.Beclomethasone dipropionate has the chemical name9-chloro-11b,17,21-trihydroxy-16b-methylpregna-1,4-diene-3,20-doine17,21-dipropionateand the following structural formula:

The compound may be a white powder with a molecular weight of 521.25;and is very slightly soluble in water (Physicians' Desk Reference®),very soluble in chloroform, and freely soluble in acetone and inalcohol.

Particle Size Distribution Profile

The formulations of the present invention may comprise acocorticosteroid (e.g., beclometasone diproprionate) having thefollowing particle size distribution profile: about 10% or less of thedrug substance particles have a particle size of less than 0.75 microns;about 25% or less of the drug substance particles have a particle sizeof less than 1.5 microns; about 50% or less of the drug substanceparticles have a particle size of less than 2.0 microns; about 75% orless of the drug substance particles have a particle size of less than3.5 microns; about 90% or less of the drug substance particles have aparticle size of less than 5.0 microns; and greater than 90% or about100% of the drug substance particles have a particle size of less than10 microns. Surprisingly, it has been discovered that formulationscontaining a cocorticosteroid (e.g., beclomethasone diproprionate)having a particle size distribution profile falling within the aboveranges provide increased bioavailability over conventional formulationswhen administered via the intranasal route to a subject in need thereof,as well as increased and prolonged drug efficacy.

As used herein, particle size refers to an average particle size asmeasured by conventional particle size measuring techniques well knownto those skilled in the art, such as sedimentation field flowfractionation, photon correlation spectroscopy, or disk centrifugation,among other techniques.

In an alternative embodiment, the formulation of the present inventioncomprises a drug substance having the following particle sizedistribution profile: about 10% of the drug substance particles have aparticle size of less than 0.35 microns; about 25% of the drug substanceparticles have a particle size of less than 0.70 microns; about 50% ofthe drug substance particles have a particle size of less than 1.25microns; about 75% of the drug substance particles have a particle sizeof less than 2.0 microns; about 90% of the drug substance particles havea particle size of less than 3.0 microns; and greater than 90% or about100% of the drug substance particles have a particle size of less than6.5 microns. Preferably, the drug substance is beclomethasonedipropionate.

The formulations of the present invention may also comprise a drugsubstance having the following particle size distribution profile: about10% of the drug substance particles have a particle size less than 0.75,0.70, 0.60, 0.55, 0.50, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, 0.10, or0.05 microns; about 25% of the drug substance particles have a particlesize less than 1.5, 1.45, 1.40, 1.35, 1.30, 1.25, 1.20, 1.15, 1.10,1.05, 1.0, 0.95, 0.90, 0.85, 0.80, 0.75, 0.70, 0.65, 0.60, 0.55, 0.50,0.45, 0.40, 0.35, 0.30, 0.25, 0.20, 0.15, or 0.10 microns; about 50% ofthe drug substance particles have a particle size less than 2.5, 2.4,2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, 0.9,0.8, 0.7, or 0.6 microns. About 75% of the drug substance particles havea particle size less than 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7,2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0, 1.9, 1.8, 1.7, 1.6, 1.5, or 1.4microns; about 90% of the drug substance particles have a particle sizeless than 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9,3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, 2.5,2.4, 2.3, 2.2, or 2.1 microns and greater than 90% or about 100% of thedrug substance particles have a particle size less than 10, 9.5, 9.0,8.5, 8.0, 7.5, 7.0, 6.5, 6.0, 5.5, 5.0, 4.5, or 0.40 microns.

In one preferred embodiment, the formulation of the present inventioncomprises a drug substance having the following particle sizedistribution profile: about 10% of the drug substance particles have aparticle size less than 0.40 microns; about 25% of the drug substanceparticles have a particle size less than 0.70 microns; about 50% of thedrug substance particles have a particle size less than 1.3 microns;about 75% of the drug substance particles have a particle size less than2.0 microns; about 90% of the drug substance particles have a particlesize less than 3.0 microns; greater than 90% or about 100% of the drugsubstance particles have a particle size less than 6.0 microns.

In another alternative embodiment, the formulation of the presentinvention comprises a drug substance having the following particle sizedistribution profile: about 10% of the drug substance particles have aparticle size less than 0.60 microns; 25% of the drug substanceparticles have a particle size less than 0.90 microns; about 50% of thedrug substance particles have a particle size less than 1.5 microns;about 75% of the drug substance particles have a particle size less than2.5 microns; about 90% of the drug substance particles have a particlesize less than 3.5 microns; greater than 90% or about 100% of the drugsubstance particles have a particle size less than 6.0 microns.

In another alternative embodiment, greater than 90% or about 100% of theparticles have a particle size less than 15 microns, preferably lessthan 10 microns, more preferably less than 8 microns, most preferablyless than 7 microns. In another preferred embodiment, greater than 90%or about 100% of the particles have a particle size between 4 and 7microns or 5 and 6 microns. In another embodiment, greater than 90% orabout 100% of the particles have a particle size less than 10 microns,preferably less than 7 microns; less than 6 microns; less than 5microns, or less than 4 microns.

In one alternative embodiment, such aqueous suspension formulations aresuitable for direct administration to a subject via the nasal passagesand represent an improvement over conventional techniques foradministering the drug substances intranasally, particularlybeclomethasone. Specifically, due to the specific particle sizedistribution profile of the drug substance, the present formulationsprovide increased bioavailability of the drug substance as well asincreased efficacy and/or prolonged therapeutic effect of the drugsubstance.

The formulation of the present invention may be provided as an aqueoussuspension. As used herein, suspension include, but are not limited to,mixtures of fine, non-settling particles of a solid within a liquidphase. In one embodiment, the formulation of the present invention is anaqueous suspension comprising about 0.005% to about 10% w/w of a drugsubstance, calculated on a dry basis. In alternate embodiment, the drugsubstance is beclomethasone.

In another alternate embodiment, the formulation of the presentinvention is an aqueous suspension comprising about 0.005% to about 5%,or 0.01% to about 2.5% w/w of a drug substance, calculated on a drybasis. In a preferred embodiment, the formulation is an aqueoussuspension comprising about 0.025% to about 1.0% w/w of a drugsubstance, calculated on a dry basis having the particular particle sizedistribution profile of the present invention, wherein the drugsubstance is preferably beclomethasone. Even more preferably, theformulation is an aqueous suspension comprising about 0.04% to about0.05% w/w of a drug substance, calculated on a dry basis. In a preferredembodiment, the drug substance is beclomethasone dipropionate.

In a preferred embodiment, the formulation of the present invention isan aqueous suspension comprising about 0.042% by weight ofbeclomethasone dipropionate, calculated on a dry basis, wherein thebeclomethasone dipropionate has the following particle size distributionrange: about 10% of the particles have a particle size of less than 0.35microns; about 25% of the particles have a particle size of less than0.65 microns; about 50% of the particles have a particle size of lessthan 1.20 microns; about 75% of the particles have a particle size ofless than 1.9 microns; about 90% of the particles have a particle sizeof less than 2.85 microns; and greater than 90% or about 100% of theparticles have a particle size of less than 6.0 microns.

In one alternative embodiment, the nasal formulation of the presentinvention may comprise a preservative, suspending agent, wetting agent,tonicity agent and/or diluent. In one embodiment, the formulationsprovided herein may comprise from about 0.01% to about 90%, or about0.01% to about 50%, or about 0.01% to about 25%, or about 0.01% to about10%, or about 0.01% to about 5% of one or more pharmacologicallysuitable suspending fluids which is physiologically acceptable uponadministration intranasally. Pharmacologically suitable fluids for useherein include, but are not limited to, polar solvents, including, butnot limited to, compounds that contain hydroxyl groups or other polargroups. Solvents include, but are not limited to, water or alcohols,such as ethanol, isopropanol, and glycols including propylene glycol,polyethylene glycol, polypropylene glycol, glycol ether, glycerol andpolyoxyethylene alcohols. Polar solvents also include protic solvents,including, but not limited to, water, aqueous saline solutions with oneor more pharmaceutically acceptable salt(s), alcohols, glycols or amixture there of. In one alternative embodiment, the water for use inthe present formulations should meet or exceed the applicable regulatoryrequirements for use in inhaled drugs.

In certain embodiments herein, the formulations of the present inventionhave a pH of about 2.0 to about 9.0. Optionally, the formulations of thepresent invention may contain a pH buffer. For example, a buffer maycomprise any known pharmacologically suitable buffers which arephysiologically acceptable upon administration intranasally. The buffermay be added to maintain the pH of the formulation between about 3.0 andabout 7.0, for example.

Sterility or adequate antimicrobial preservation may be provided as partof the present formulations. Since certain formulations of the presentinvention are intended to be administered intranasally, it is preferredthat they be free of pathogenic organisms. A benefit of a sterile liquidsuspension is that it reduces the possibility of introducingcontaminants into the individual when the suspension formulation isadministered intranasally, thereby reducing the chance of anopportunistic infection. Processes which may be considered for achievingsterility may include any appropriate sterilization steps known in theart. In one embodiment, the drug substance (e.g., beclomethasone) isproduced under sterile conditions, the micronization is performed in asterile environment, and the mixing and packaging is conducted understerile conditions. In alternative embodiment, the formulations of thepresent invention may be sterile filtered and filled in vials, includingunit dose vials providing sterile unit dose formulations which are usedin a nasal spray device for example. Each unit dose vial may be sterileand is suitably administered without contaminating other vials or thenext dose. In one alternative embodiment, one or more ingredients in thepresent formulation may be sterilized by steam, gamma radiation orprepared using or mixing sterile steroidal powder and other sterileingredients where appropriate. Also, the formulations may be preparedand handled under sterile conditions, or may be sterilized before orafter packaging.

In addition to or in lieu of sterilization, the formulations of thepresent invention may contain a pharmaceutically acceptable preservativeto minimize the possibility of microbial contamination. Additionally, apharmaceutically-acceptable preservative may be used in the presentformulations to increase the stability of the formulations. It should benoted, however, that any preservative must be chosen for inhalationsafety, as the treated tissues may be sensitive to irritants.Preservatives suitable for use herein include, but are not limited to,those that protect the solution from contamination with pathogenicparticles, including phenylethyl alcohol, benzalkonium chloride, benzoicacid, or benzoates such as sodium benzoate. Preferably, the preservativefor use in the present formulations is benzalkonium chloride orphenylethyl alcohol. In certain embodiments, the formulations hereincomprise from about 0.01% and about 1.0% w/w of benzalkonium chloride,or from about 0.01% and about 1% v/w phenylethyl alcohol. Preservingagents may also be present in an amount from about 0.01% to about 1%,preferably about 0.002% to about 0.02% by total weight or volume of thecomposition.

The formulations provided herein may also comprise from about 0.01% toabout 90%, or about 0.01% to about 50%, or about 0.01% to about 25%, orabout 0.01% to about 10%, or about 0.01% to about 1% w/w of one or moreemulsifing agent, wetting agent or suspending agent. Such agents for useherein include, but are not limited to, polyoxyethylene sorbitan fattyesters or polysorbates, including, but not limited to, polyethylenesorbitan monooleate (Polysorbate 80), polysorbate 20 (polyoxyethylene(20) sorbitan monolaurate), polysorbate 65 (polyoxyethylene (20)sorbitan tristearate), polyoxyethylene (20) sorbitan mono-oleate,polyoxyethylene (20) sorbitan monopalmitate, polyoxyethylene (20)sorbitan monostearate; lecithins; alginic acid; sodium alginate;potassium alginate; ammonium alginate; calcium alginate;propane-1,2-diol alginate; agar; carrageenan; locust bean gum; guar gum;tragacanth; acacia; xanthan gum; karaya gum; pectin; amidated pectin;ammonium phosphatides; microcrystalline cellulose; methylcellulose;hydroxypropylcellulose; hydroxypropylmethylcellulose;ethylmethylcellulose; carboxymethylcellulose; sodium, potassium andcalcium salts of fatty acids; mono-and di-glycerides of fatty acids;acetic acid esters of mono- and di-glycerides of fatty acids; lacticacid esters of mono-and di-glycerides of fatty acids; citric acid estersof mono-and di-glycerides of fatty acids; tartaric acid esters ofmono-and di-glycerides of fatty acids; mono-and diacetyltartaric acidesters of mono-and di-glycerides of fatty acids; mixed acetic andtartaric acid esters of mono-and di-glycerides of fatty acids; sucroseesters of fatty acids; sucroglycerides; polyglycerol esters of fattyacids; polyglycerol esters of polycondensed fatty acids of castor oil;propane-1,2-diol esters of fatty acids; sodium stearoyl-2-lactylate;calcium stearoyl-2-lactylate; stearoyl tartrate; sorbitan monostearate;sorbitan tristearate; sorbitan monolaurate; sorbitan monooleate;sorbitan monopalmitate; extract of quillaia; polyglycerol esters ofdimerised fatty acids of soya bean oil; oxidatively polymerised soyabean oil; and pectin extract. In certain embodiments herein, the presentformulations comprise polysorbate 80, microcrystalline cellulose,carboxymethylcellulose sodium and/or dextrose.

The present formulations may further comprise from about 0.01% to about90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about0.01% to about 10%, or about 0.01% to about 1% of one or more excipientsand additives which are pharmacologically suitable. Excipients andadditives generally have no pharmacological activity, or at least noundesirable pharmacological activity. The concentration of these mayvary with the selected agent, although the presence or absence of theseagents, or their concentration is not an essential feature of theinvention. The excipients and additives may include, but are not limitedto, surfactants, moisturizers, stabilizers, complexing agents,antioxidants, or other additives known in the art. Complexing agentsinclude, but are not limited to, ethylenediaminetetraacetic acid (EDTA)or a salt thereof, such as the disodium salt, citric acid,nitrilotriacetic acid and the salts thereof. In another embodiment,particularly in the suspension formulations provided herein, thecomplexing agent is sodium edetate. In one embodiment, the compositionscontain sodium edetate at a concentration of about 0.05 mg/mL to about0.5 mg/mL, or about 0.1 mg/mL to about 0.2 mg/mL. Also, for example, theformulations of the present invention may comprise from about 0.001% toabout 5% by weight of a humectant to inhibit drying of the mucousmembrane and to prevent irritation. Any of a variety ofpharmaceutically-acceptable humectants can be employed, includingsorbitol, propylene glycol, polyethylene glycol, glycerol or mixturesthereof, for example.

The formulations provided herein also may comprise about 0.01% to about90%, or about 0.01% to about 50%, or about 0.01% to about 25%, or about0.01% to about 10%, or about 0.01% to about 10% of one or more solventsor co-solvents to increase the solubility of any of the components ofthe present formulation. Solvents or co-solvents for use herein include,but are not limited to, hydroxylated solvents or otherpharmaceutically-acceptable polar solvents, such as alcohols includingisopropyl alcohol, glycols such as propylene glycol, polyethyleneglycol, polypropylene glycol, glycol ether, glycerol, andpolyoxyethylene alcohols. In another embodiment, the formulations of thepresent invention may comprise one or more conventional diluents knownin the art. The preferred diluent is water.

Tonicity agents may include, but are not limited to, sodium chloride,potassium chloride, zinc chloride, calcium chloride and mixturesthereof. Other osmotic adjusting agents may also include, but are notlimited to, mannitol, glycerol, and dextrose or mixtures thereof. In analternative embodiment, the present formulation may comprise about 0.01%to about 10% w/w, or about 1% to about 8% w/w, or 1% to about 6% w/w,preferably about 5.0% w/w. The preferred tonicity agent is Dextrose,anhydrous.

In one alternative embodiment, the formulations of the present inventionare stable. As used herein, the stability of formulations providedherein refers to the length of time at a given temperature that greaterthan 80%, 85%, 90% or 95% of the initial amount of drug substance, e.g.,beclomethasone, is present in the formulation. For example, theformulations provided herein may be stored between about 15° C. andabout 30° C., and remain stable for at least 1, 2, 12, 18, 24 or 36months. Also, the formulations may be suitable for administration to asubject in need thereof after storage for more than 1, 2, 12, 18, 24 or36 months at 25°. Also, in another alternative embodiment, usingArrhenius Kinetics, more than 80%, or more than 85%, or more than 90%,or more than 95% of the initial amount of drug substance (e.g.,beclomethasone) remains after storage of the formulations for more than1, 2, 12, 18, 24 or 36 months between about 15° C. and about 30° C.

The formulations of the present invention may be manufactured in anyconventional manner by thoroughly mixing the ingredients describedherein at ambient or elevated temperatures in order to achievesolubility of ingredients where appropriate.

The preparation of a drug substance having the particle sizedistribution profile of the present invention may be obtained by anyconventional means known in the art, or by minor modification of suchmeans. For example, suspensions of drug particles can rapidly undergoparticulate size reduction when subjected to “jet milling” (highpressure particle in liquid milling) techniques. Other known methods forreducing particle size into the micrometer range include mechanicalmilling, the application of ultrasonic energy and other techniques.

In one alternative embodiment, the present invention provides a methodfor the treatment of rhinitis comprising the step of administering to asubject in need thereof a therapeutically effective amount of theformulations disclosed herein. In one embodiment, the method of thepresent invention comprises administering to a subject in need thereof atherapeutically effective amount of drug substance, wherein the drugsubstance is beclomethasone, the drug substance having a particle sizedistribution profile described herein. Preferably, the drug substance isbeclomethasone dipropionate. In certain embodiments, the subject is amammal. In other embodiments, the subject is a human.

In one embodiment, the present invention provides a method for treatingrhinitis comprising the step of administering to a subject in needthereof a therapeutically effective amount of the present formulation,wherein the formulation comprises an aqueous suspension comprising about0.005% to about 5% by weight of beclomethasone having a particle sizedistribution profile described herein. In certain embodiments, theformulation is sterile, contains a preservative and/or is stable.

In other embodiments, the present invention provides a method fortreating rhinitis comprising the step of administering the formulationsdisclosed herein intranasally to a subject in need thereof. Preferably,the formulation is administered to a subject via nasal spray, preferablya metered-dose spray pump. The metered-dose spray pump may be manuallyoperated, such that each actuation of the pump delivers a single dosageof the drug substance to the subject. In another embodiment, theformulation of the present invention may be administered via a nasalspray pump or atomizing spray pump.

In another alternative embodiment, the nasal spray comprises ametered-dose, manual pump spray unit (e.g. metering atomizing pump)comprising a microcrystalline suspension of beclomethasone dipropionate,monohydrate equivalent to 0.02% to about 2.0%, preferably about 0.10% toabout 0.05%, more preferably about 0.042% w/w beclomethasonedipropionate, calculated on a dried basis, in an aqueous medium. Inanother alternative embodiment, said suspension comprisesmicrocrystalline cellulose, carboxymethyl cellulose sodium, dextrose,benzalkonium chloride, polysorbate 80, and 0.25% v/w phenylethylalcohol. An acid, preferably hydrochloric acid, may be added to adjustpH. The pH may be between 4.5 and 7.0. After initial priming (3-4actuations), each actuation of the manual pump may deliver from a nasaladapter about 10 mg to about 1,000 mg, preferably about 100 mg to about500 mg, most preferably about 100 mg of suspension containingbeclomethasone dipropionate, monohydrate equivalent to about 10 mcg toabout 500 mcg, or about 10 mcg to about 100 mcg, or about 30 mcg toabout 60 mcg, preferably about 40 mcg to about 50 mcg, more preferablyabout 42 mcg of beclomethasone dipropionate, calculated on a dry basis.Each bottle containing the present formulations of nasal spray mayprovide about 20-600 metered doses, preferably 100 to about 300 doses,more preferably at least 200 metered doses.

In an alternative embodiment, the administration of the presentformulations may comprise 1, 2, 3, 4, 5, 6, 7 or 8 inhalations of thepresent formulation in each nostril one, two, three, four or five timesa day. Each inhalation may comprise about 1 mcg to about 400 mcg, orabout 1 mcg to about 100 mcg, preferably about 30 mcg to about 100 mcg,more preferably about 30 mcg to about 80 mcg, or about 30 mcg to about50 mcg most preferably about 42 mcg. The total dose per day of the drugsubstance may comprise about 10 mcg and about 4000 mcg, about 10 mcg toabout 1,000 mcg, about 10 mcg to about 500 mcg, or about 100 mcg toabout 900 mcg preferably about 100 mcg to about 500 mcg, or morepreferably about 150 mcg to about 400 mcg.

In another alternative embodiment, the administration of the presentformulations may comprise 1 and only 1 inhalation in each nostril a day.In one alternative embodiment, the starting dosage of the presentformulation may comprise one and only 1 inhalation in each nostril oncedaily. In another alternative embodiment, such starting dosage isappropriate for adults. Each inhalation may comprise about 5 mcg toabout 100 mcg, preferably from about 30 mcg to 70 mcg, more preferablyabout 42 mcg of beclomethasone, calculated on a dry basis.

Administering 1 and only 1 inhalation in each nostril is more beneficialand advantageous over conventional regimens of the prior art, whichrequire more inhalations in each nostril per day. For example, otherknown nasal spray products, e.g., beclomethasone products, require 1 or2 inhalations (42 to 84 mcg) in each nostril twice a day (total dose,168-336 mcg/day). In contrast, formulations of the present invention mayrequire 1 and only 1 inhalation in each nostril a day. By limiting thedosage, or amount of inhalations per day, individuals would likelycomply with the regimen or regular dosage schedule to achieve adequaterelief, thereby improving the patient's quality of life as compared withother traditional treatments. Further, administering fewer inhalationsprovide the individual more opportunity to take other medications duringtreatment, such as, for example, other oral or inhaled steroids, thusreducing likelihood of overdosing or cross reaction between medications.Further, providing fewer inhalations would reduce the likelihood ofaddiction to the drug substance in the nasal formulation. Moreover,administering fewer inhalations may reduce toxicity and the adverseevents associated with 2 or more inhalations of a particular drugsubstance in each nostril per day. Also, individuals hypersensitive to 2or more doses of a particular drug substance would benefit fromreceiving 1 and only 1 dose per day.

The present formulations can be packaged as kits or systems, whichoptionally contain other components, including instructions for use ofthe formulations. Articles of manufacture, containing packaging materialand a formulation provided herein, which is useful for treatment,prevention or amelioration of one or more symptoms of a medicalcondition, disorder or disease (e.g. rhinitis) and a label indicatingthat the formulation is used for treatment, prevention or ameliorationof one or more symptoms of diseases or disorders associated withundesired and/or uncontrolled rhinitis.

EXAMPLES

The following example is included for illustrative purposes only and isnot intended to limit the scope of the invention.

A double-blind, double-dummy, randomized, placebo-controlled, study wasperformed to assess the safety and efficacy of the formulations of thepresent invention (Dey BD), in adolescent and adult patients withseasonal allergic rhinitis. The objectives of this study were (1) todetermine the safety and efficacy of Dey BD compared with placebo during2 weeks of treatment in adult and adolescent patients with seasonalallergic rhinitis (SAR); and (2) to establish the comparability of DeyBD with Beconase AQ®. Nasal Spray during 2 weeks of treatment in adultsand adolescent patients. Currently, Beconase AQ®. is commerciallyavailable from GlaxoSmithKlein.

Both Dey and Beconase AQ® comprised a microcrystalline suspension ofbeclomethasone dipropionate, monohydrate equivalent to 0.042% w/wbeclomethasone dipropionate, calculated on a dried basis, in an aqueousmedium. However, the beclomethasone used in Dey BD nasal spray wasderived and/or purchased from a different source from that used inBeconase AQ®. Otherwise, both nasal sprays contained the same excipientsand additives in the same amounts. Also, Dey BD nasal spray and BeconaseAQ® was administered by the same metered-dose, manual pump spray. Forboth the BD nasal spray and Beconase AQ®, each activation of the manualpump delivered about 42 mcg of beclomethasone dipropionate.

The study was conducted during the 2001 fall allergy season (local fallpollen) in the United States. The study duration was 3 weeks andconsisted of 2 phases: a 1-week baseline screening period followed by a2-week randomized double-blind treatment phase. Patients were seen on anoutpatient basis on Day −7, Day 1, Day 7, and Day 14. Initial baselineassessments occurred 1 week prior (Day −7±2 days) to randomization totreatment. Patients were first assigned a patient number and thenscreened for eligibility based on study entrance criteria and completionof baseline assessments. If eligible, patients were then given standardoral antihistamine as a rescue medication and a Patient Total NasalSymptom Score (TNSS) Diary. Patients recorded daily TNSS (sum of thesigns and symptoms for runny nose, nasal congestion, sneezing, and itchynose) in their diaries rating each on a scale of zero to 3 with zerobeing no symptoms present and 3 being severe symptoms present, as wellas the amount of oral antihistamine taken. One week later, at theconclusion of the baseline assessments, the patients returned to thestudy site and were re-evaluated for eligibility. Patients who did notcomplete the diaries or no longer met the inclusion/exclusion criteriawere discontinued.

To be included in the study, patients must have been diagnosed with SARand must have met the following inclusion criteria:

-   -   At least a 2-yr history of moderate-to-severe SAR due to fall        pollen;    -   Individuals 12 years of age and older;    -   Confirmed IgE-mediated hypersensitivity to local fall pollen        within last 12 months (a positive result is required);    -   Minimum TNSS of 8 of a maximum of 12 on at least 3 days during        the baseline period, one of which must have been within 3 days        of Day 1;    -   If receiving immunotherapy, a stable maintenance regimen for 30        days prior to study enrollment;    -   General good health and free of disease or concomitant treatment        that could interfere with interpretation of study results;    -   Written informed consent/pediatric assent; and,    -   Willingness to comply with study procedures.

Patients who met all criteria were then randomized to 1 of 5 treatmentgroups: (1) Dey BD Nasal Spray (0.042%) Low Dose—1 spray of Bottle 1(Dey BD) in each nostril followed by 1 spray of Bottle 2 (placebo) ineach nostril twice daily (morning and evening); (2) Dey BD Nasal Spray(0.042%) High Dose—1 spray of Bottle 1 (Dey BD) in each nostril followedby 1 spray of Bottle 2 (Dey BD) in each nostril twice daily (morning andevening); (3) Beconase AQ® Low Dose—1 spray of Bottle 1 (Beconase AQ®)in each nostril followed by 1 spray of Bottle 2 (placebo) in eachnostril twice daily (morning and evening); (4) Beconase AQ® High Dose—1spray of Bottle 1 (Beconase AQ®) in each nostril followed by 1 spray ofBottle 2 (Beconase AQ®) twice daily (morning and evening); and (5)placebo—1 spray of Bottle 1 (placebo) in each nostril followed by 1spray of Bottle 2 (placebo) in each nostril twice daily (morning andevening).

The double-blind treatment phase (Day 1 through 14) consisted of twicedaily self-administered treatment (1 spray from each bottle into eachnostril per administration). On Days 7 and 14 (or at early termination),patients returned to the study sites and were evaluated. Efficacyassessments included reflective and instantaneous TNSS daily diaryinformation, patient and physician global evaluations, and use of rescuemedication.

The primary endpoint for this study was the change from baseline in apatient's 12-hour (AM and PM combined) reflective TNSS over a 2-weektreatment period. The primary endpoint analysis was the comparison ofDey BD High Dose versus placebo. TNSS consisted of the sum of the12-hour assessment scores for runny nose, nasal congestion, sneezing,and itchy nose recorded twice daily on the Patient's TNSS Diary card.Baseline was defined as the average of the run-in period 12-hour (AMplus PM combined) reflective TNSS from the 7 calendar days 12 dayspreceding Day 1.

The secondary endpoints for this study were as follows:

-   -   The change from baseline in a patient's combined AM plus PM        12-hour reflective TNSS overall (Days 2-14);    -   The change from baseline in a patient's combined AM plus PM        12-hour reflective TNSS at Days 7 and 14;    -   The change from baseline in a patient's AM 12-hour reflective        TNSS;    -   The change from baseline in a patient's PM 12-hour reflective        TNSS;    -   The change from baseline to 1-week and 2-week postbaseline in        area under the concentration curve (AUC)s of patient's combined        AM plus PM 12-hour reflective TNSS;    -   The change from baseline to 1-week and 2-week postbaseline in        AUC of patient's AM 12-hour reflective TNSS;    -   The change from baseline to 1-week and 2-week postbaseline in        AUC of patient's PM 12-hour reflective TNSS;    -   The change from baseline in patient's AM plus PM combined        instantaneous TNSS;    -   The change from baseline in patient's AM instantaneous TNSS;    -   The change from baseline in patient's PM instantaneous TNSS;    -   Patient global evaluation of change in SAR signs and symptoms;    -   Physician global evaluation of change in SAR signs and symptoms;        and,    -   Use of rescue medication.    -   Secondary efficacy endpoints were compared across all treatment        groups.

With respect to efficacy, both reflective and instantaneous change frombaseline in 12-hour (AM plus PM, combined and individual) TNSS forprimary and secondary variables at Week 1 and Week 2 were comparedacross the groups using a mixed effect analysis of variance (ANOVA)model. Area under the curve (AUC) of the 12-hour (AM plus PM, combinedand individual) reflective TNSS was calculated for the baseline periodand Week 1 and Week 2 (over Days 2-14) postbaseline using a trapezoidalmethod. The change from baseline was compared across the groups using asimilar ANOVA model. The patient's and physician's global evaluation ofchange from baseline in SAR symptoms was compared between the groupsusing a one-way ANOVA model. Frequency of rescue medication use, as wellas the percentage of patients needing rescue medication, was comparedacross the groups using Fisher's exact test. The average number oftablets of rescue medication was compared using an ANOVA model. Allstatistical analyses were performed for both Intent-to-Treat (ITT) andper-protocol populations. Missing observations in the ITT Populationwere imputed using the last observation carried forward (LOCF) method.All inferential statistics were conducted against a two-sidedalternative hypothesis at 0.05 level of significance.

A total of 674 patients were randomized to 1 of 5 treatment groups (136Dey BD High Dose, 136 Dey BD Low Dose, 135 Beconase AQ® High Dose, 129Beconase AQ® Low Dose, or 138 placebo groups); 661 (98.07%) patientscompleted the study and 13 (1.93%) patients discontinued. The mostcommon reasons for discontinuation were AE and withdrawal of consent (4/13 patients each, 30.77%). More than 85% of the patient population wasWhite, more than 60% were female with a mean age across groups rangingfrom 33.62 to 36.79 years and a mean antigen challenge result rangingfrom 8.6 to 9.4 mm. The majority of patients had a negative history ofbeclomethasone usage (mean range=82.61-87.60%).

All active treatment groups (Dey BD and Beconase AQ®) demonstratedreductions in TNSS over the 2-week treatment period. Regardless of whichefficacy endpoint was examined (i.e., 12-hour reflective TNSS,instantaneous TNSS, change in AUC), the Treatment effect was highlysignificant as was the Day effect (p=0.0000) indicating improvement inTNSS. Both Dey BD and Beconase AQ® High Dose groups were statisticallysuperior to placebo for both primary and secondary efficacy endpointanalyses, as were Dey BD Low Dose and Beconase AQ® Low Dose treatmentgroups. Treatment-by-Day interaction (overall Days 2-14) andTreatment-by-Week interaction effects were not statistically significantindicating that the treatment groups behaved similarly for the durationof the study, except for the magnitude of improvement in TNSS. There wasno statistical difference between Dey BD and Beconase AQ® High Dosegroups for any efficacy endpoint analysis. However, the Dey BD Low Dosegroup was found to be consistently statistically superior to theBeconase AQ® Low Dose group in relieving symptoms of SAR. Results ofanalyses for the Per Protocol Population paralleled those of the ITTPopulation for all efficacy variables.

FIG. 1 shows the change from baseline in AM and PM reflective TNSS overtime in the ITT population over the 14 day study period. FIG. 2 showsthe change from baseline in AM reflective TNSS over time in the ITTpopulation over the 14 day study period. FIG. 3 shows the change frombaseline in PM reflective TNSS over time in the ITT population over the14 day study period. FIG. 4 shows the change from baseline in AM and PMreflective TNSS over time in the PP population over the 14 day studyperiod.

In FIGS. 1-4, the efficacy of the nasal formulations is expressed as thechange from baseline (pretreatment) in a composite score of nasalsymptoms (e.g. runny nose, sneezing, nasal itching and congestion)referred to as total nasal symptom scores (TNSS). The change frombaseline in TNSS scores is expressed in absolute units (rather tanpercent change from baseline). Using an analysis of variance model(ANOVA), the least square mean (LS Mean) for the baseline (positivevalue) and change from baseline (negative value if symptoms improve) areobtained. The higher the negative value seen in the LS Mean, the greaterwas the change (improvement) in TNSS.

Table 1 shows the particle size distribution of the beclomethasoneparticles in Dey BD, wherein the particle size is in microns. Table 2shows the quantitative composition of Dey BD. TABLE 1 Dey BD Nasal SprayParticle Size Data Run 1 Run 2 Run 3 Avg D (v, 0.10) 0.29 0.27 0.32 0.29D (v, 0.25) 0.58 0.54 0.58 0.57 D (v, 0.50) 1.15 1.10 1.06 1.10 D (v,0.75) 1.84 1.81 1.81 1.82 D (v, 0.90) 2.73 2.60 2.75 2.69 D (v, 1.00)5.69 5.69 — 5.69

TABLE 2 Quantitative Composition of Beclomethasone DipropionateMonohydrate Nasal Spray. 0.042% Concentration in Amount per Amount perAmount per Component Function Drug Product Spray* Bottle** KilogramBeclomethasone Dipropionate Active Ingredient 0.042% w/w^(•) 42 .μg^(•)11 mg^(•) 0.42 g^(•) Monohydrate, USP Benzalkonium Chloride Preservative0.020% w/w^(••) 20 μg^(••) 5.3 mg^(••) 0.20 g^(••) Solution, 50%, NFMicrocrystalline Cellulose/ Suspending Agent 1.50% w/w^(•) 1.50 mg^(•)398 mg^(•) 15.0 g^(•) Carboxymethyl-cellulose Sodium, NF Polysorbate 80,NF Wetting Agent 0.0050% w/w 5.0 .μg 1.3 mg 0.050 g Phenylethyl Alcohol,USP Preservative 0.25% v/w 255 μg^(•••) 68 mg^(•••) 2.6 g^(•••)Dextrose, anhydrous, USP Tonicity Agent 5.000% w/w 5.000 mg 1.325 g50.00 g Hydrochloric Acid, 1N To adjust pH as required as required asrequired as required Purified Water, USP Diluent N/A 93.18 mg 24.69 g931.5 gV/w = volume to weight;w/w = weight to weight^(•)Dry Basis^(••)Expressed as Benzalkonium Chloride^(•••)Based on Density of 1.019 g PEA/mL*Target Spray Weight = 100 mg**Target Fill = 26.5 g per Bottle

The Figures and attachments herein are presented for illustrativepurposes only. They are not intended to limit the scope of theinvention. Further, it should be understood that various changes andmodifications to the presently preferred embodiment described hereinwill be apparent to those skilled in the art. Such changes andmodifications can be made without departing from the spirit and scope ofthe present invention and without diminishing its attendant advantages.It is therefore intended that such changes and modifications be coveredby the appended claims. Also, the invention may suitably comprise,consist of or consist essentially of the elements or steps describedherein. Further, the invention described herein suitably may comprise orbe practiced in the absence of any element or step which is notspecifically disclosed herein. Further, one or more step describedherein may be performed simultaneously with another step.

1. A nasal pharmaceutical formulation comprising a therapeuticallyeffective amount of beclomethasone, wherein the formulation comprisesabout 0.005% to about 5% by weight beclomethasone having the followingparticle size distribution profile: (i) about 10% of the beclomethasoneparticles have a particle size of less than 0.75 microns; (ii) about 25%of the beclomethasone particles have a particle size of less than 1.5microns; (iii) about 50% of the beclomethasone particles have a particlesize of less than 2.0 microns; (iv) about 75% of the beclomethasoneparticles have a particle size of less than 3.5 microns; and (v) about90% of the beclomethasone particles have a particle size of less than5.0 microns, and wherein the beclomethasone is suitable foradministration to an individual via intranasally.
 2. The nasalpharmaceutical formulation of claim 1, wherein the beclomethasone hasthe following particle size distribution profile: (i) about 10% of thebeclomethasone particles have a particle size of less than 0.50 microns;(ii) about 25% of the beclomethasone particles have a particle size ofless than 1.0 microns; (iii) about 50% of the beclomethasone particleshave a particle size of less than 1.5 microns; (iv) about 75% of thebeclomethasone particles have a particle size of less than 2.5 microns;and (v) about 90% of the beclomethasone particles have a particle sizeof less than 4.0 microns.
 3. The nasal pharmaceutical formulation ofclaim 1, wherein the formulation comprises an aqueous suspension that isdeliverable via an atomizing device.
 4. The nasal pharmaceuticalformulation of claim 3, wherein the atomizing device comprises a metereddose spray pump.
 5. The nasal pharmaceutical formulation of claim 1,wherein the formulation is suspended in a liquid propellant.
 6. Thenasal pharmaceutical formulation of claim 1, wherein the nasalpharmaceutical formulation is sterile.
 7. The nasal pharmaceuticalformulation of claim 1, wherein the nasal pharmaceutical formulationfurther comprises a preservative.
 8. The nasal pharmaceuticalformulation of claim 1, wherein the formulation is stable.
 9. The nasalpharmaceutical formulation of claim 1, wherein the formulation comprisesabout 0.01% to about 1% by weight of beclomethasone.
 10. The nasalpharmaceutical formulation of claim 1, wherein the formulation comprisesabout 0.04% to about 0.045% by weight of the beclomethasone.
 11. A nasalspray formulation comprising: an aqueous suspension having about 0.005%to about 5% by weight beclomethasone and having the following particlesize distribution profile: (i) about 10% of the beclomethasone particleshave a particle size of less than 0.40 microns; (ii) about 25% of thebeclomethasone particles have a particle size of less than 0.70 microns;(iii) about 50% of the beclomethasone particles have a particle size ofless than 1.30 microns; (iv) about 75% of the beclomethasone particleshave a particle size of less than 2.0 microns; and (v) about 90% of thebeclomethasone particles have a particle size of less than 3.0 microns.12. The nasal pharmaceutical formulation of claim 11, wherein theformulation comprises about 0.01% to about 1% by weight of thebeclomathasone.
 13. The nasal pharmaceutical formulation of claim 11,wherein the formulation comprises about 0.04% to about 0.045% by weightof the beclomethasone.
 14. The nasal spray formulation according toclaim 11, wherein the formulation is deliverable via a metered dosespray pump.
 15. The nasal spray formulation according to claim 14,wherein ambient air is a propelling agent for delivering each spray ofthe metered-dose spray pump.
 16. The nasal spray formulation accordingto claim 14, wherein each spray of the metered-dose spray pump deliversat least about 1 mcg of beclomethasone.
 17. The nasal spray formulationof claim 14, wherein each spray of the metered-dose spray pump deliversabout 1 mcg to about 100 mcg of beclomethasone.
 18. The nasal sprayformulation of claim 11, further comprising a preservative, suspendingagent, wetting agent, buffer, diluent, or combinations thereof.
 19. Thenasal spray formulation of claim 11, wherein the formulation furthercomprises one or more of the following compounds: (a) microcrystallinecellulose; (b) carboxymethyl cellulose sodium; (c) dextrose; (d)benzalkonium chloride; (e) polysarbate 80; and (f) phenylethyl alcohol.20. The nasal spray formulation of claim 11, wherein the formulation issuspended in a suspending fluid comprising water, alcohol, glycol, orcombinations thereof.
 21. The nasal spray formulation of claim 11,wherein the formulation includes an emulsifying agent, wetting agent,suspending agent, or combinations thereof.
 22. The nasal sprayformulation of claim 11, wherein the beclomethasone has the followingparticle size distribution profile: (i) about 10% of the particles havea particle size of less than 0.35 microns; (ii) about 25% of theparticles have a particle size of less than 0.65 microns; (iii) about50% of the particles have a particle size of less than 1.20 microns;(iv) about 75% of the particles have a particle size of less than 1.9microns; (v) about 90% of the particles have a particle size of lessthan 2.85 microns; and greater than 90% of the particles have a particlesize of less than 6.0 microns.
 23. A method of treating one or moresymptoms of rhinitis in an individual, said method comprising the stepsof applying to the individual's nasal mucosa a formulation comprisingabout 0.005% to about 5% by weight beclomethasone having the followingparticle size distribution profile: (i) about 10% of the beclomethasoneparticles have a particle size of less than 0.75 microns; (ii) about 25%of the beclomethasone particles have a particle size of less than 1.5microns; (iii) about 50% of the beclomethasone particles have a particlesize of less than 2.0 microns; (iv) about 75% of the beclomethasoneparticles have a particle size of less than 3.5 microns; and (v) about90% of the beclomethasone particles have a particle size of less than5.0 microns, and wherein the beclomethasone is suitable foradministration to an individual via intranasally.
 24. The method ofclaim 23, wherein the step of applying further comprises delivering atleast about 1 mcg of beclomethasone to the individual's nasal mucosa.25. The method of claim 23, wherein the step of applying furthercomprises delivering about 1 mcg to about 100 mcg of beclomethasone tothe individual's nasal mucosa.
 26. The method of claim 23, wherein theformulation comprises an aqueous suspension and the step of applyingfurther comprises atomizing the aqueous suspension.
 27. The method ofclaim 23, wherein the beclomethasone has the following particle sizedistribution profile: (i) about 10% of the beclomethasone particles havea particle size of less than 0.50 microns; (ii) about 25% of thebeclomethasone particles have a particle size of less than 1.0 microns;(iii) about 50% of the beclomethasone particles have a particle size ofless than 1.5 microns; (iv) about 75% of the beclomethasone particleshave a particle size of less than 2.5 microns; and (v) about 90% of thebeclomethasone particles have a particle size of less than 4.0 microns.28. The method of claim 23, wherein the beclomethasone has the followingparticle size distribution profile: (i) about 10% of the particles havea particle size of less than 0.35 microns; (ii) about 25% of theparticles have a particle size of less than 0.65 microns; (iii) about50% of the particles have a particle size of less than 1.20 microns;(iv) about 75% of the particles have a particle size of less than 1.9microns; (v) about 90% of the particles have a particle size of lessthan 2.85 microns; and greater than 90% of the particles have a particlesize of less than 6.0 microns.
 29. The method of claim 23, whereinformulation is applied via a metered-dose, manual pump spray unit. 30.The method of claim 23, wherein the formulation comprises about 0.042%w/w beclomethasone disproportionate, calculated on a dried basis, in anaqueous medium.